PROJECT SUMMARY/ABSTRACT The long-term objective of this project is to understand how genes specify the development and functioning of a behavioral system. The anatomically simple neuromuscular system of the nematode Caenorhabditis elegans consists of diverse types of neurons and muscles while being sufficiently small and simple to allow a complete description of its cells, neural circuits and cell lineage, facilitating the identification of anatomical and developmental abnormalities caused by mutations. Studies of the C. elegans egg-laying system and of the neuromuscular systems that control behaviors coordinately regulated with egg laying, such as feeding behavior, offer opportunities for the analysis of a broad variety of fundamental biological problems of relevance to many human disorders. The major issue that this project will address is how C. elegans responds behaviorally to oxygen stresses, as oxygen is essential for animal life but also can be damaging to tissues and cause disease. This project will analyze how two distinct oxygen stresses -- oxygen deprivation and reactive oxygen species ? induce aversive behavioral responses. First, what are the molecular mechanisms that mediate behavioral responses to oxygen deprivation, which profoundly affects cellular and organismic physiology and is responsible for the cardiac damage in heart attacks as well as for disorders of the kidneys, nervous system and other organs? The major pathway that mediates responses to chronic oxygen deprivation has been implicated in many human disorders and has defined major therapeutic targets for cancer. This aim will identify new components of this important pathway, including potential new drug targets and drug leads, and also reveal how this pathway controls animal physiology and behavior. Second, how do reactive oxygen species cause the neural circuits of the C. elegans feeding organ, the pharynx, to reverse phayngeal pumping actions to drive spitting instead of feeding, thereby preventing the ingestion of toxic oxygen species? The C. elegans pharyngeal nervous system is the simplest known and longest- studied connectome in biology, yet much about how it functions remains unknown. Connectomics, the study of nervous-system connectivity maps, promises critical insights into human brain organization and function, is a major theme of the NIH BRAIN Initiative and is crucial for our understanding of many neurologic and neuropsychiatric disorders. However, an anatomical connectome is insufficient to reveal how the nervous system drives behavior. This aim will comprehensively probe the circuit, cellular, and molecular properties by which the pharyngeal nervous system responds to reactive oxygen species, relate these properties to the simplest and most completely defined connectome in biology and reveal the types of information needed to complement a connectome to establish how a nervous system drives behavior.